This invention relates to novel chroman compounds, pharmaceutical compositions containing such compounds, and methods of treating beta-3 adrenoreceptor-mediated conditions with such compositions.
Adrenoreceptors, or adrenergic receptors, are sites on effector organs that are innervated by postganglionic adrenergic fibers of the sympathetic nervous system, and are classified as either alpha-adrenergic or beta-adrenergic receptors. Alpha-adrenergic receptors respond to norepinephrine and to such blocking agents as phenoxybenzamine and phentolamine, whereas beta-adrenergic receptors respond to epinephrine and to such blocking agents as propranolol.
Beta-adrenergic receptors are sub-classified as beta-1, beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation causes cardiostimulation, whereas beta-2 stimulation causes bronchodilation and vasodilation.
Beta-3 receptors are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis and energy expenditure. Agonists of beta-3 adrenoreceptors are known to be useful in the treatment of hyperglycemia (diabetes) and obesity in mammals, as well as in the treatment of gastrointestinal disorders and neurogenetic inflammation (U.S. Pat. No. 5,561,142). Additionally, they are known to lower triglyceride and cholesterol levels and to raise high-density lipoprotein levels in mammals (U.S. Pat. No. 5,451,677). Accordingly, they are useful in the treatment of conditions such as hypertriglyceridemia, hypercholesterolemia, and in lowering high-density lipoprotein levels. They also may be useful in treating patients with Syndrome X, impaired fasting glucose, and/or impaired glucose tolerance, as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions.
Additionally, it is also believed that the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
It has now been found that certain novel chroman derivatives are effective as beta-3 agonists and are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.

wherein
R is independently
hydroxy,
oxo,
halo,
cyano,
nitro,
C1-C10 alkyl,
C1-C10 haloalkyl,
CF3,
NR1R1,
SR1,
OR1,
SO2R2,
OCOR2,
NR1COR2,
COR2,
NR1SO2R,
phenyl, or
a 5- or 6-membered heterocycle with from 1 to 4 heteroatoms selected from O, S, and N;
each cyclic moiety being optionally substituted with
hydroxy,
R1,
halo,
cyano,
NR1R1,
SR1,
CF3,
OR1,
C3-C8 cycloalkyl,
NR1COR2,
COR2,
SO2R2,
OCOR2,
NR1SO2R2,
C1-C10 alkyl, or
C1-C10 alkoxy;
R1 is
hydrogen,
(CH2)dxe2x80x94Oxe2x80x94(CH2)dR5 where each d is selected independently, or
C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from
hydroxy,
halo,
CO2C1-C4-alkyl,
CO2H,
C1-C10 alkoxy,
S(O)bC1-C10 alkyl,
S(O)b-phenyl optionally substituted with halo, C1-C4alkyl, C1-C4 alkoxy, SO2xe2x80x94C1-C4alkyl, or CO2 C1-C4alkyl; or
phenyl optionally substituted with CO2C1-C4-alkyl, CO2H, halo, or C1-C10 alkyl; or
C3-C8 cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, CO2C1-C4-alkyl, and CO2H, and
when two R1 groups are attached to N as NR1R1, these R1 groups may form together with the nitrogen to which they are attached, a heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;
R2 is
R1,
OR1,
NR1R1,
NHS(O)bphenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo or nitro;
NHS(O)bnaphthyl,
NHS(O)bC1-C10 alkyl optionally substituted with fluoro up to the perfluoro level, or
a 5- or 6-membered heterocycle with one or more heteroatoms selected from O, S, and N, said heterocyclic moiety being optionally substituted with R1;
R3 is hydrogen, C1-C10 alkyl, or COR2;
R4 is hydrogen, C1-C10 alkyl, C1-C10 alkyl-phenyl, or C1-C10 alkyl-pyridyl;
R5 is hydrogen or COOH;
R6 is
hydrogen,
C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from halo, phenyl, or phenyl-COR2, or
C1-C10 alkyl-S(O)bC1-C10 alkyl optionally substituted with COR2 or C3-C8 cycloalkyl;
Ar is
phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to a phenyl, or
a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;
Y is
halo,
NO2,
R6,
SR1,
S(O)b-phenyl-CO2R1, 
where, when the two R4 groups attached to the same C are both alkyl, they optionally may be joined so that, when taken together with the C to which they are attached, they form a spiro ring of 3, 5, or 6 C atoms, or where the R4 attached to N and one R4 attached to the adjacent C are both alkyl, they optionally may be joined so that, taken together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring;
with the proviso that when e is 1, at least one R4 group must be C1-C10 alkyl-phenyl or C1-C10 alkyl-pyridyl, or two R4 groups must form one of said spiro or heterocyclic ring moieties,
phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or
a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring,
each cyclic moiety being optionally substituted with one or more substituents independently selected from
COR2,
CONR1S(O)2R9,
COCH2SO2-thiazolyl optionally substituted with alkyl or amino,
halo,
NO2,
OR1,
R1,
SR1,
Oxe2x80x94C1-C6-alkyl substituted by C3-C6-cycloalkyl,
O-phenyl optionally substituted by SO2CH3,
SO2NH2,
SO2NR1R7,
NR1R1,
NR1COC1-C6alkyl, 
C1-C10COR2,
phenyl optionally substituted with halo, C1-C4 alkyl, or C1-C4 alkoxy,
tetrazolo;
R7 is
phenyl or heteroaryl containing 3-6 C and 1-3 O, N, or S atoms, each optionally substituted by C1-C4 alkyl, CN, NO2, COxe2x80x94C1-C4alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl,
COxe2x80x94R8, 
R8 is
C1-C6 alkyl optionally substituted with C1-C4 alkoxy, N(CH3)2, or one or two CF3,
C3-C6-cycloalkyl,
phenyl optionally substituted with C1-C4 alkoxy, halo, or C1-C4 alkyl,
NH-phenyl optionally substituted with C1-C4 alkyl, halo, C1-C4 alkoxy, or C1-C4 haloalkoxy,
NH-cyclohexyl;
R9 is
C3-C6 cycloalkyl,
thienyl optionally substituted with C1-C4 alkyl or isoxazolyl,
pyridyl optionally substituted with xe2x80x94SO2xe2x80x94C1-C4 alkyl,
pyrazolyl optionally substituted with halo or C1-C4 alkyl,
isoxazolyl optionally substituted with C1-C4 alkyl, or 
a is 0, 1, 2, 3, 4, or 5;
b is 0, 1, or 2;
d is 1, 2, or 3;
e is 1 or 2;
and pharmaceutically acceptable salts and esters thereof.
The terms identified above have the following meaning throughout:
C1-C10 alkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms, which may be saturated, unsaturated, or partially saturated. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, as well as vinyl, allyl, propynyl, butenyl, butadienyl, isopropenyl, methyleneyl, ethylenyl, propenyl, ethynyl, and the like.
C1-C10 haloalkyl means straight or branched chain alkyl groups having from about one to about ten carbon atoms where any Cxe2x80x94C bond may be saturated or unsaturated, the alkyl groups being substituted at any available carbon atom with one or more halogen atoms, and includes such groups as trifluoromethyl, trichloromethyl, pentafluoroethyl, fluoromethyl, 6-chlorohexyl, and the like.
The term C1-C10 alkoxy means straight or branched chain alkoxy groups having from one to about ten carbon atoms where any Cxe2x80x94C bond may be saturated or unsaturated, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
The term C1-C10 alkylthio means straight or branched chain alkylthio groups having from one to about ten carbon atoms where any Cxe2x80x94C bond may be saturated or unsaturated, and includes such groups as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
C3-C8 cycloalkyl means saturated mono cyclic alkyl groups of from 3 to about 8 carbon atoms, and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
Halo includes fluoro, chloro, bromo, and iodo, unless specifically stated otherwise.
R, R2, Ar, and Y each include any 5- or 6-membered saturated or unsaturated heterocyclic group having any combination of one or more N, S, or O atoms with the point of attachment being at any available position on the heterocyclic ring. Where there is more than one heteroatom in a single cyclic group, each heteroatom shall be chosen independently of any other heteroatom, in each occurrence, with the proviso that any single heterocyclic ring may not contain more than two oxygen or sulfur atoms. These moieties include such 5-membered heterocylic groups as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dioxolyl, dithiolanyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, triazolinyl, triazolidinyl, oxadiazolyl, thiadiazolyl, furazanyl, tetrazolyl, and the like. It also includes such 6-membered heterocyclic rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyranyl, thiopyranyl, triazinyl, dioxanyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl, and the like
Ar and Y also each include phenyl fused to any 5- or 6-membered heterocyclic ring described above to form a bicyclic moiety, which may be saturated or unsaturated and may have any combination of one or more N, S, or O atoms with the point of attachment being any at available position on the phenyl ring. These include such phenyl fused 5-membered heterocyclic groups as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzothiadiazolinyl, benzisothiazolyl, benzisothiazolinyl, benzotriazolyl, benzoxadiazolyl, benzoxadiazolinyl, benzothiadiazolyl, benzopyrazolinyl, and the like. It also includes such phenyl fused 6-membered heterocyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
Ar also includes phenyl fused to any 5- or 6-membered heterocyclic ring to form a bicyclic moiety as described above, which is further fused on the heterocyclic ring to a second phenyl ring, forming a tricyclic system, with the point of attachment to the core structure of the compound of Formula I being at any available position of the first phenyl ring. These include such groups as carbazolyl, carbazolinyl, acridinyl, xanthenyl, phenoxathiinyl, phenoxazinyl, phenanthridinyl, dibenzofuryl, dibenzopyranyl, dibenzodioxanoyl, phenazinyl, thianthrenyl, and the like.
Ar also includes any 5- or 6-membered saturated or unsaturated heterocyclic ring having any combination of one or more N, S, or O atoms as described above, which is further fused to a phenyl ring, with the point of attachment to the core molecule of Formula I being at any available position on the heterocyclic ring. These include such phenyl-fused with 5-membered hetero-bicyclic moieties as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolizinyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzisothiazolyl, benzoisothiazolinyl, benzopyrazolinyl and the like. It also includes such phenyl-fused with 6-membered hetero-bicyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
C1-C10-alkyl-phenyl means saturated straight or branched chain alkyl groups having from one to about ten carbon atoms where the phenyl moiety is attached at any available position on the alkyl group. Examples of these moieties include benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-methyl-2-phenylethyl, 5-phenylpentyl, 4-phenylhexyl, and the like.
C1-C10-alkyl-pyridyl means straight or branched chain saturated alkyl groups having from one to about ten carbon atoms where the pyridyl moiety is attached at any available position on the alkyl group. The pyridyl group may be attached to the alkyl group from any available position on the pyridine ring. Examples of these include pyridyl, 2-(2-pyridyl)ethyl, 3-(4-pyridyl)-propyl, 2-(3-pyridyl)-propyl, 1-methyl-2-(3-pyridyl)-ethyl, 5-(3-pyridyl)-pentyl, 4-(4-pyridyl)-hexyl, and the like.
S(O)b-phenyl-CO2R1 means a phenylthio, a phenylsulfinyl, or a phenylsulfonyl group, where the CO2R1 moiety is attached at any available position on the phenyl ring.
When any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence. For example, NR1R1 may represent NH2, NHCH3, N(CH3)CH2CH2CH3, and the like.
Examples of the compound of Formula I, which are illustrative of the present invention but not limiting in any way, are listed in Table 1.
The present invention includes compounds of Formula I wherein Y is halo; R6; SR1; S(O)b-phenyl-CO2R1; or phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2, halo, NO2, OR1, R1, SR1, SO2NR1R7, NR1R1, C1-C10COR2, phenyl, or tetrazolo.
Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2, halo, NO2, OR1, R1, SR1, SO2NR1R7, NR1R1, C1-C10COR2, phenyl, or tetrazolo; and d is 1 or 2.
Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2, halo, NO2, OR1, R1, SR1, SO2NR1R7, NR1R1, C1-C10COR2, phenyl, or tetrazolo; d is 1 or 2; and Ar is phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N; or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl.
Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2, halo, OR1, R1, or NR1R1; d is 1; Ar is phenyl or a 5- or 6-membered heterocycle containing one or more N atoms; and a is 0, 1, 2, or 3.
In addition, the present invention specifically includes the following compounds:
2-[4-(ethoxycarbonyl)phenoxy]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 197);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutylbenzoic acid (Example 211);
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-2-methylbenzenesulfonamide (Example 91);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutoxybenzoic acid (Example 183);
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-4-methoxybenzenesulfonamide (Example 92);
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-1-propanesulfonamide (Example 97);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxybenzoyl)benzenesulfonamide (Example 300);
N-(2-cyano-4-nitrophenyl)-3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 259);
2-(4-chlorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 194);
N-(4,6-dimethoxy-2-pyrimidinyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulfonamide (Example 274);
2-(4-fluorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 193);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3-methoxybenzoyl)benzenesulfonamide (Example 293);
4-fluoro-N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}benzenesulfonamide (Example 295);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(4-methylphenoxy)benzoic acid (Example 195);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-phenylethyl)benzoic acid (Example 213);
3-chloro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 124);
N-(4-fluorobenzoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 295);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methoxybenzoic acid (Example 125);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-phenoxybenzoic acid (Example 192);
N-(4-cyanophenyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulfonamide (Example 262);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)-2-(trifluoromethoxy)benzenesulfonamide (Example 275);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3,3,3-trifluoropropanoyl)benzenesulfonamide (Example 284);
2-hydroxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 180);
3-((1R)-2-{[((2R)-6-{4-[({[(4-fluorophenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine (Example 327);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide (Example 249);
N-benzoyl-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 294);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-propoxybenzoic acid (Example 186);
N-({4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinyl}carbonyl)-4-methoxybenzenesulfonamide (Example 80);
3-((1R)-1-hydroxy-2-{[((2R)-6-{4-[({[(4-methylphenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)pyridine (Example 326);
3-((1R)-2-{[((2R)-6-{4-[({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine (Example 330);
N-(ethoxyacetyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 286);
N-(3,3-dimethylbutanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 287);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methyl-2-pyrimidinyl)benzenesulfonamide (Example 268);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-[4-(methylsulfonyl)phenoxy]benzoic acid (Example 198);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic acid (Example 88);
4-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid (Example 215);
N-(2,2-dimethylpropanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 292);
3-[(1R)-2-({[(2R)-6-(4-{[(anilinocarbonyl)amino]sulfonyl}phenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-hydroxyethyl]pyridine (Example 328);
2-ethoxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 185);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)benzenesulfonamide (Example 273);
3-{(1R)-2-[({(2R)-6-[4-({[(cyclohexylamino)carbonyl]amino}sulfonyl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]-1-hydroxyethyl}pyridine (Example 329);
N-(cyclopropylcarbonyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 285);
2-chloro-5-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 122);
4-[(4-[R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 148);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methylbenzoic acid (Example 149);
2-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 150);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-propoxybenzoic acid (Example 130);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isopropoxybenzoic acid (Example 188);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide (Example 265);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(4-methoxyphenoxy)benzoic acid (Example 196);
3-(cyclopropylmethoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 132);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 325);
5-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4xe2x80x2-methyl-1,1xe2x80x2-biphenyl-2-carboxylic acid (Example 205);
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide (Example 319);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3-pyridinyl)benzenesulfonamide (Example 253);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methoxybenzoic acid (Example 184);
4-chloro-N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide (Example 320);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-isobutoxybenzoic acid (Example 133);
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}methanesulfonamide (Example 321);
3-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid (Example 216);
3-[(1E)-1-hexenyl]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 128);
3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide (Example 261);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-methoxyethoxy)benzoic acid (Example 187);
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2,6-dimethylbenzoic acid (Example 121);
4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 385);
3-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 386);
(1R)-1-(6-amino-3-pyridinyl)-2-[({(2R)-6-[4-(1H-tetraazol-5-yl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]ethanol (Example 384);
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-phenyl-1,215,315,4-thiatriazole-2-carboxylic acid (Example 166);
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-furoic acid (Example 159);
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid (Example 154);
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-thiophenecarboxylic acid (Example 156);
4-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid (Example 157);
6-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid (Example 151);
5-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid (Example 142);
2-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4-pyridinecarboxylic acid (Example 158);
1-({[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]carbonyl}amino)cyclopropanecarboxylic acid (Example 366); and
4-[(2R)-2-({[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 344).
Representative salts of the compounds of Formula I include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
The esters in the present invention are non-toxic, pharmaceutically acceptable esters such as alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-C1-C5 alkyl may be used, although methyl ester is preferred. The compound of Formula I may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula I compound. The appropriate anhydride is reacted with the alcohol in the presence of an acylation catalyst such as 1,8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine. An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst. Esterification may also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of N,N-carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as 4-DMAP or pyridine.
Sensitive or reactive groups on the compound of Formula I may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification of alcohols.
The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R,S) configuration, preferably in the (R)- or (S)-configuration, whichever is most active. The configurational isomers of Formula I, in which both the hydroxyl group attached to the side chain containing the Arxe2x80x94X-moiety and the (CH2)d group attached to the dihydrochromenyl ring are above the plane, as depicted below, are preferred. 
All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.
Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (=Z-) or trans (=E-) form, and both isomeric forms are encompassed within the scope of this invention.
The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific Ar and Y moieties and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.
For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991. For example, after preparation of a compound according to Reaction Scheme 1, in order to enable purification of the end product by, for example, flash chromatography, compounds of Formula I wherein R3 is H, may be selectively protected, for example, as a carbamate derivative obtained by, for example, treatment with a reagent such as di-tert-butyl dicarbonate or other means known in the art. After purification, the carbamate group can easily be removed by treatment with an acid such as HCl or trifluoroacetic acid by means known in the art.
In the Reaction Schemes below, one skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. When specific reagents or solvents are shown in a Reaction Scheme, therefore, they are meant to be illustrative examples of conditions desirable for the execution of that particular Reaction Scheme. Abbreviations not identified in accompanying text are listed later in this disclosure under xe2x80x9cAbbreviations and Acronyms.xe2x80x9d
In general, Formula I compounds may be prepared by standard techniques known in the art and by known processes analogous thereto. In particular, three such standard methods may be used, the selection of which may be based, among other considerations, upon the availability of the required individual starting materials. These three methods are illustrated in Reaction Schemes 1, 2, and 3 below.
The compounds of Formula I where each variable may be any moiety within that variable""s definition may be synthesized according to Reaction Scheme 1 wherein an appropriate epoxide 1a, or chlorohydrin 1b (preparation of 1a is described in WO 99/32475) is coupled with the appropriate amine 2 (preparation of 2 is described below in Reaction Schemes 12, 13, and 14). This reaction of Reaction Scheme 1 is typically carried out in an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in an alcohol such as ethanol, isopropanol, or propanol at temperature from about xe2x88x9210xc2x0 C. to reflux. Compounds in which R3 is other than hydrogen may be prepared by reaction of compound I in which R3 is H, by selective N-alkylation of N-acylation reactions with known compounds of formula R3-halo (where R3 is acyl or alkyl) or [R3]2O (where R3 is acyl). Protection of the hydroxyl group, for example as a TBDMS ether, may be required prior to N-alkylation reactions; O-deprotection is carried out under standard conditions well known in the art. 
Alternatively, Formula I compounds, where each variable may be any moiety within that variables definition, except that d=1, may be prepared by a reductive amination as shown in Reaction Scheme 2. Reaction of an aldehyde of Formula 4 (preparation described below in Reaction Scheme 9) with an amino alcohol of Formula 3 (preparation described in WO 98/32475) followed by reduction gives the desired transformation to Formula Ia compounds. Compounds in which R3 is other than hydrogen may be prepared by reaction of compound Ia in which R3 is H by selective N-alkylation or N-acylation reactions with known compounds of formula R3-halo (where R3 is alkyl or acyl) or [R3]2O (where R3 is acyl). Protection of the hydroxyl group, for example, as a TBDMS ether, may be required prior to N-alkylation reactions. O-deprotection is carried out under standard conditions well known in the art. 
A third general route to Formula I compounds, where each variable may be any moiety within that variable""s definition except that d=1, is shown in Reaction Scheme 3. An amino alcohol 3 and a carboxylic acid 5 (preparation described in Reaction Schemes 10 and 11) are coupled to provide an amide of Formula 6. Reduction of the Formula 6 amides with an appropriate reagent such as borane-dimethylsulfide complex provides the Formula I compounds where R3 is H. Formula I compounds in which R3 is other than H may be similarly prepared as described above for Reaction Schemes 1 and 2. 
Reaction Scheme 4 shows that compounds of Formula I or Formula Ia where Y is any alkenyl, cycloalkenyl, phenyl, or a 5-or 6-membered heterocyclic ring may be prepared from compounds of Formula I or Formula Ia where Y is a halogen, using the following additional methods described below. For example, a compound of Formula I, wherein Y is iodo, may be prepared by Reaction Scheme 1 using corresponding starting materials 2 or 4, where Y is iodo, each of which may be prepared by Reaction Schemes 12 or 9, respectively. The resulting Formula I compound is then protected by standard methods to give a compound of Formula 7a. The compound of Formula 7a is then converted to the boronic ester 8, which is then subjected to Suzuki coupling reactions with a halo-Y compound, in which Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5-or 6-membered heterocycle to provide Formula 7 compounds as shown in Reaction Scheme 4. Deprotection of Formula 7 compounds by acid or fluoride-catalyzed hydrolysis provides the corresponding Formula I compounds. 
The coupling may also be performed in the reverse manner, that is, a boronic ester derivative 10 prepared from a halophenyl compound 9 may be added to the iodo compound of Formula 7b, as shown in Reaction Scheme 5 to give Formula Ib compounds. 
Formula I compounds in which Y is an aryl group further substituted by a S(O)bR2 or NHS(O)bR2 group may be prepared by elaboration of the corresponding Formula 7 compounds in which Y is an aryl group substituted by CO2H as shown in Reaction Scheme 6.
Formula I compounds wherein Y is 
and R1 and R3 are as described above, may be prepared by a sequence shown in Reaction Scheme 7. The iodo compound of Formula 7a may be converted to the carboxylic acid of Formula 7c by palladium-catalyzed carboxylation. This may then be coupled with an amino acid using standard peptide synthesis techniques, deprotected and hydrolyzed to give compounds of Formula Ic. This method may be repeated to give Formula I compounds where Y is 
by an analogous sequence of reactions performed on the Formula Ic compounds. 
Formula Id compounds of Reaction Scheme 8 may be prepared according to Reaction Scheme 1 or 3, starting from the known Formula 5 compound (U.S. Pat. No. 6,051,586) in which Yxe2x95x90NO2. Other Formula I compounds wherein Y is NR1R1 may be prepared from the nitro compound of Formula Id by reduction to Ie followed by dialkylation with the appropriate alkylating agents, such as R1-halo, R1-OTs, or R1-OMs to If (Reaction Scheme 7). 
Reaction Scheme 9 shows how other Formula I compounds in which Y is S(O)bPh-CO2R1 and b is 0 may be prepared by diazotization of Ie and nucleophilic displacement with a arylthiol to give arylthioethers of Formula Ih. Oxidation of the Formula Ih compound with mCPBA or Oxone(copyright) gives the Formula Ii compound in which Y is xe2x80x94S(O)bPh-CO2R1 and b=1 or the Formula Ij compound in which Y is xe2x80x94S(O)bPhxe2x80x94CO2R1 and b=2, depending on the number of equivalents of oxidant used in the reaction.
Formula I compounds in which Y is SR1 may be similarly prepared by methods analogous to Reaction Scheme 9, by substituting HSR1 in place of the arylthiol in the first step. 
The salts and esters of the Formula I compounds of the invention may be readily prepared by conventional chemical processes.
The starting materials required to carry out the above described reactions (e.g., epoxides 1a, chlorohydrins 1b, amines 2, amino alcohols 3, aldehydes 4, and carboxylic acids 5) are in many cases commercially available or may be readily prepared by methods known to those skilled in the art. The following routes are exemplary of such methods, but are not intended to be limiting in any way.
The epoxides 1a of Reaction Scheme 1 are commercially available or may be prepared according to one of the many procedures described in the literature known to those skilled in the art. For example, as described in WO 99/32475, the epoxides of formula 1a may be prepared by the reaction of an aryl methyl ketone with a selective halogenating agent such as NBS, followed by ketone reduction with, for example, sodium borohydride to a give a chlorohydrin 1b (a halo alcohol). Base-catalyzed cyclization of this alcohol with, for example, potassium carbonate, gives the epoxides of formula 1a. This method is general for the conversion of substituted methyl aryl ketones of general formula (R)axe2x80x94Arxe2x80x94C(xe2x95x90O)CH3 to the corresponding epoxides of formula 1a.
The amino alcohols 3 may be prepared by ring opening of the epoxides 1a with a nitrogen nucleophile, such as phthalimide, in the presence of a base to form an intermediate which may be cleaved or hydrolyzed as described in WO 98/32475. This sequence is general for conversion of epoxides of formula 1a to the amino alcohols of formula 3.
Synthesis of aldehyde starting materials of Formula 4 may be accomplished from the carboxylic acid of Formula 5 by reduction with borane followed by oxidation, for example, under Swern conditions as shown in Reaction Scheme 10. This method is compatible with a wide variety of Y groups, although in some cases, a protecting group may also be employed and removed in a subsequent step. 
The carboxylic acids of Formula 5 are generally available from the known unsubstituted chroman carboxylic acid 5a (WO 99/32476) by various aromatic substitution reactions at the 6-position of the chroman ring and further elaboration of these products. For example, halogenation (e.g., iodination) of 5a gives the 6-iodo compound 5b and nitration gives predominantly the 6-nitro analog 5c (U.S. Pat. No. 6,051,586) as shown in Reaction Scheme 11.
Compounds of Formula 5 where Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle may be prepared by Suzuki coupling of a halo-Y group to an iodo chroman boronic ester 12 prepared from the iodo chroman acid 5b. 
The amine starting materials of Formula 2, in which d=1, are generally available by standard methods involving conversion of a carboxylic acid 5 to an amide of Formula 13. Reduction with borane or further conversion of the Formula 13 amide to the nitrile of Formula 14 and then reduction by hydrogenation gives the desired Formula 2a compounds. This sequence is shown in Reaction Scheme 13 for Formula 2 amines wherein d=1 and R3 is H. Formula 2 amines in which R3 is other than H may be prepared by standard alkylation or acylation methods known in the art. 
Formula 2 amines in which d is 2 or 3 may be prepared by standard homologation sequences of a variety of known intermediates where d=1. For example, aldehydes of Formula 4 can undergo an alkyl chain extension according to well known procedures such as that described by Wittig et al., (Chem. Ber., 2514, 1962) and the process may be repeated in order to prepare the acetic and propionic acid homologues of Formula 5 by a method analogous to Reaction Scheme 13, to provide a variety of Formula 2 amines in which d=2 or 3.
Formula 2 amines in which Y is other than hydrogen or halo may be prepared by palladium-catalyzed coupling reactions on the N-protected amine of Formula 15a followed by deprotection, as shown in Reaction Scheme 14. Formula 2 amines prepared in this way in which the Y group is substituted by an acid, ester, alcohol, ketone, sulfide, or nitro group may provide additional Formula 2 amines by manipulation of those functional groups by directed hydrolysis, esterification, reduction, oxidation, or reduction reactions of the Y group. 
Similarly, the amine 2c, after protection, may be directly substituted at the 6-position of the chroman under Friedel-Crafts alkylation conditions to provide the compounds of Formula 15 in which Y is any alkyl or cycloalkyl group. An example of this where Y is an optionally substituted alkanoic acid group (15c) is shown in Reaction Scheme 15.
Alcohol intermediates of Formula 11 in which Y is other than hydrogen or halo may also be prepared from the iodo alcohol 11a by the previously described Suzuki coupling methodology as shown in Reaction Scheme 16. This may be accomplished either directly or via a 4-step sequence involving protection of the alcohol to 16a, for example, as a t-butyldimethylsilyl ether, conversion of the iodide to the boronic ester, Suzuki coupling to 16, and finally deprotection to 11.
The halo-Y compounds used in Reaction Schemes 12, 14, and 16 where halo is iodo, chloro, or bromo and Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle, are either commercially available or synthesized by standard methods known to those skilled in the art. One such standard method is direct halogenation of compounds of formula Hxe2x80x94Y which are either commercially available or known in the art. Other methods include the functional group conversion of HOxe2x80x94Y or H2Nxe2x80x94Y compounds to halo-Y or TfOxe2x80x94Y compounds by standard substitution methods.
Particular illustrations of this are the preparation of halo-Y compounds of Formula 9b or 9c, where Y represents an oxazole or a thiazole, prepared by direct halogenation of the unsubstituted compound or by diazotization of a corresponding amino group as shown in Reaction Scheme 17.
The heterocyclic intermediates 17 and 18 used to prepare 9b and 9c are accessible by standard methods from acyclic materials. Three examples of such heterocycles are shown in Reaction Schemes 18, 19, and 20. 
Using a combination of the above Reaction Schemes and the knowledge of one skilled in the art, all of compounds of Formula I may be prepared.
The following specific examples are presented to further illustrate the invention described herein, but they are not intended nor should they be construed to limit the scope of the invention in any way.
When the following abbreviations are used herein, they have the following meaning:
HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mmxc3x9723 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile, and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.
Combinatorial/parallel reactions were carried out in 8-mL glass vials with Teflon-lined screw caps, or in a polypropylene reaction block consisting of a 8xc3x9712 matrix of ninety-six 2.0-mL reaction wells, with each reaction well incorporating a 15-45 micron polyethylene frit. Reaction blocks of this type are commercially available as FlexChem(trademark) reactor blocks from Robbins Scientific Corporation, Sunnyvale, Calif. The reactor blocks are sealed with rubber gaskets and a clamping device, and can be heated with mixing by rotation in an oven (Robbins Scientific).